19-3281254-T-TCCGG

Variant names:

• chr19-3281254-T-TCCGG
• rs1057518402
• NM_021938.4:c.661_664dupCGGC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_021938.4(CELF5):​c.661_664dupCGGC​(p.Arg222ProfsTer181) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CELF5 NM_021938.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.509

Genes affected

CELF5 (HGNC:14058): (CUGBP Elav-like family member 5) This gene encodes a member of the the CELF/BRUNOL protein family, which contain two N-terminal RNA recognition motif (RRM) domains, one C-terminal RRM domain, and a divergent segment of 160-230 aa between the second and third RRM domains. Members of this protein family regulate pre-mRNA alternative splicing and may also be involved in mRNA editing and translation. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELF5	NM_021938.4	c.661_664dupCGGC	p.Arg222ProfsTer181	frameshift_variant	Exon 6 of 13	ENST00000292672.7	NP_068757.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CELF5	ENST00000292672.7	c.661_664dupCGGC	p.Arg222ProfsTer181	frameshift_variant	Exon 6 of 13	1	NM_021938.4	ENSP00000292672.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.661_664dupCGGC variant in the CELF5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.661_664dupCGGC variant causes a frameshift starting with codon Arginine 222, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 158 of the new reading frame, denoted p.Arg222ProfsX158. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.661_664dupCGGC variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.661_664dupCGGC as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057518402; hg19: chr19-3281252;